Context: Radiation therapy is a potentially curative treatment for corticotroph adenomas refractory to surgery. Protons have an advantage over photons (x-rays) by depositing energy at the target with no exit dose, providing a lower dose to adjacent normal tissues. Until recently, proton stereotactic radiotherapy (PSR) was available at only two US centers; use will increase as proton facilities are under development.

Objective: To evaluate the efficacy and safety of PSR for persistent Cushing's disease and Nelson's syndrome.

Design: Retrospective review of 38 patients (33 with Cushing's disease and 5 with Nelson's syndrome) treated between 1992 and 2005.

Participants: All patients had transsphenoidal surgery without biochemical cure. Four had previous irradiation with photons. The patients with Nelson's syndrome underwent bilateral adrenalectomy 29–228 (median 40) months prior to PSR.

Intervention: Single fraction PSR was delivered at a median dose of 20 (range 15–20) Cobalt Gray Equivalents on one treatment day.

Main Outcome Measures: Complete response (CR) was defined as sustained ( 3 months) normalization of urinary free cortisol off medical therapy. CR in Nelson's syndrome was based on normalization of plasma corticotropin.

Results: At a median follow-up of 62 (range 20–136) months, CR was achieved in 5 (100%) patients with Nelson's syndrome and 17 (52%) patients with Cushing's disease. Among all patients with CR, median time to CR was 18 (range, 5–49) months. No secondary tumors were noted on follow-up MRI scans, and there was no clinical evidence of optic nerve damage, seizure, or brain injury. Seventeen patients (52%) developed new pituitary deficits.

Conclusions: PSR is effective for patients with persistent corticotroph adenomas with low morbidity after a median of 62 months; longer follow-up is warranted for late radiation-related sequelae.